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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2202-2207
Follicular Large Cell Lymphoma: An Aggressive Lymphoma That Often
Presents With Favorable Prognostic Features
By
J. Rodriguez,
P. McLaughlin,
F.B. Hagemeister,
L. Fayad,
M.A. Rodriguez,
M. Santiago,
M. Hess,
J. Romaguera, and
F. Cabanillas
From the University of Texas M.D. Anderson Cancer Center,
Houston, TX.
 |
ABSTRACT |
It is debated whether follicular large cell lymphoma (FLCL) has a
clinical behavior that is distinct from indolent follicular lymphomas,
and whether there is a subset of patients who can be potentially cured.
We report here our experience with 100 FLCL patients treated at our
institution since 1984 with three successive programs. We evaluated the
predictive value of pretreatment clinical features, including two risk
models, the Tumor Score System and the International Prognostic Index
(IPI). With a median follow-up of 67 months, the 5-year survival is
72% and the failure-free survival (FFS) is 67%, with a possible
plateau in the FFS curve, particularly for patients with stage I-III
disease. Features associated with shorter survival included age  60,
elevated lactic dehydrogenase (LDH) or
beta-2-microglobulin ( 2M), advanced stage, and bone marrow
involvement. Stage III patients had significantly better survival than
stage IV patients (P < .05). By the IPI and Tumor Score
System, 80% of the patients were in the lower risk groups; both
systems stratified patients into prognostic groups. Patients with FLCL
have clinical features and response to treatment similar to that
reported for diffuse large cell lymphoma. Prognostic risk systems for
aggressive lymphomas are useful for FLCL. A meaningful fraction of
patients may possibly be cured when treated as aggressive lymphomas.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
FOLLICULAR LARGE cell lymphoma (FLCL) is
an uncommon disease, representing 3% to 7% of non-Hodgkin's
lymphomas.1 FLCL is distinguished from other follicular
lymphomas both in the Working Formulation, in which it is classified as
intermediate grade, and in the Revised European-American Lymphoma
(REAL) classification, in which it is designated as follicle center,
follicular, grade 3.2 But controversy exists concerning the
number of large cells and extent of follicular formation that are
required to establish the diagnosis; even the REAL classification
provides no precise criteria to determine the grade. Thus, the
difficulty in subcategorizing the follicular lymphomas is acknowledged
in the literature.3,4 Investigators in many recent
series5-7 required that 50% of the cells present be large
cells, with a predominance of large noncleaved cells to confirm the
diagnosis. Martin et al5 have recently assessed the utility
of the Berard method of grading follicular lymphomas in an analysis of
106 patients with follicular lymphomas, and found that the histologic
classification according to the Berard criteria was the only
independent predictor of survival.
A coherent view of FLCL has been limited not only by the disparate
diagnostic criteria, but also by the relative infrequency of FLCL and
the small and retrospective nature of most FLCL reports in the
literature. In the last 10 to 15 years, FLCL has usually been treated
as an intermediate-grade lymphoma, with the same therapeutic strategy
as for diffuse large cell lymphoma (DLCL).5-14 Reported
responses, failure-free survival (FFS), and survival have been similar
to DLCL in many series, but some investigators have observed a pattern
of late relapse that parallels the natural history of other follicular
lymphomas.9,11,14 Thus, some issues are unresolved,
especially whether there is a true plateau in the failure-free survival
curve, and consequently whether there is a subset of FLCL patients who
are potentially cured.
Analysis of clinical factors of proven prognostic value in the
aggressive lymphomas has been insufficiently studied in FLCL because of
the low number of FLCL patients in reported series. We report herein
our experience with 100 patients with FLCL, uniformly treated on three
protocols for intermediate-grade lymphoma at M.D. Anderson from 1984 until the present. We analyze the response, FFS, and survival of these
patients. We aim to identify important prognostic factors and to test
the accuracy, in FLCL, of current prognostic models developed for
aggressive lymphomas. With this large number of patients with long-term
follow-up, we also identify patients who may possibly be cured of their
disease with current therapy.
| |
MATERIALS AND METHODS |
Patients.
One hundred patients with FLCL were treated with three successive
programs designed for intermediate-grade lymphoma by the Working
Formulation. These 100 patients represent 17% of the 605 patients with
follicular lymphoma seen in our institution since 1984. The histologic
criteria required the presence of follicular formation and greater than
15 cells per high-power field being of the large cell
variety.4 We used the Ann Arbor classification to stage the
disease: staging studies included documentation of clinical disease,
complete blood cell count, chemistries, serum beta-2-microglobulin
(2M) for most patients, chest x-ray, bone marrow biopsy and
aspirate, computed tomography (CT) scan of the abdomen and pelvis, and
CT scan of the chest or other tests as indicated.
Treatment programs.
Patients were treated according to three successive risk-adapted
strategies. From 1984 to 1988, 47 patients were treated on a protocol
that called for CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine,
prednisone, bleomycin) and radiotherapy (XRT) for stage I-II patients,
and CHOP-Bleo alternating with CMED (cyclophosphamide, methotrexate,
etoposide, dexamethasone) for patients with more advanced
stage.15 From 1988 on, good-risk patients received CHOP-Bleo alternating with OPEN (vincristine, prednisone, etoposide, mitoxantrone). High-risk patients (N = 22) from 1988 on received an
alternating triple therapy (ATT) program of 3 non-cross-resistant regimens in rotation, 1 based on an anthracycline plus alkylator, 1 based on ara-C and cisplatin, and 1 based on ifosfamide and etoposide.16 The model for risk evolved during this time
period from a "tumor burden" model to a "tumor score"
system.17,18 Human immunodeficiency virus (HIV)-positive
patients and patients who had an antecedent malignancy whose prognosis
was poor or who had received previous chemotherapy were not eligible. A
cardiac ejection fraction greater than 50% measured by
echocardiography or cardiac multigated angiogram (MUGA)
scan was required. Patients signed the appropriate consent forms
according to institutional guidelines.
Follow-up.
The follow-up of the patients was every 3 months during the first year,
every 4 months during the next 2 years, every 6 months in the fourth
and fifth years, and yearly afterwards. Patients were evaluated by
physical examination, blood chemistries including lactic dehydrogenase
(LDH) and 2M, periodic bone marrow biopsy, and radiologic studies
including chest x-ray and CT scans of the abdomen and pelvis, and
chest, when appropriate.
Variables.
Variables tested for their importance as predictors of the outcome
were: age, sex, presence of B symptoms, Ann Arbor Stage, Zubrod
performance status, LDH, 2M, bone marrow involvement, platelets,
white blood cell count (WBC), hemoglobin (Hgb), presence of bulky
disease, and number of extranodal sites. Cut-offs were as previously
described.18,19 The two risk systems tested were the
International Prognostic Index (IPI)19 and Tumor
Score.18 Briefly, the Tumor Score system divides the
population into two risk groups by assigning one point for the presence
of each of five variables: Ann Arbor Stage III-IV, B symptoms, LDH > 10% above the upper limit of normal, 2M 3 µg/dL, and
each site of bulky disease. As previously reported, patients with
scores of 0 to 2 are low risk, and 3 defines high risk.
Endpoints and statistical analysis.
The evaluation of response was performed according to standard
criteria. CR was defined as the disappearance of all signs and symptoms
of disease both clinically and radiographically. Partial remission (PR)
was defined as greater than 50% reduction in the sum of the products
of the two greatest perpendicular diameters of all measurable
lesions.20 Survival and FFS were measured from the time of
initial therapy to death or failure, respectively. Failures included
patients who relapsed after CR, progressed after PR or less, had
treatment stopped because of toxicity, or who died from the lymphoma or
treatment-related toxicity.21
Survival and FFS curves were calculated by the Kaplan-Meier
method.22 Seven patients who died of tumor-unrelated deaths and were without any sign of relapse of their disease, as well as three
patients who were lost to follow up at 2, 6, and 8 years after the
diagnosis were censored at that time. Differences among the curves in
each tested variable were performed by the log-rank test.20
Differences in response according to prognostic variables were tested
by the chi-square test of independence or trend as appropriate.20
| |
RESULTS |
Patient characteristics.
The median age of the patients in this series was 59 years (range, 24 to 84). There were 53 women and 47 men. Sixty-five patients had a
homogeneous pattern of FLCL. Thirty patients had areas of DLCL along
with unequivocal FLCL, and 5 patients had areas of FLCL and follicular
small cleaved cell lymphoma (FSC) in the same lymph node. Eighteen
patients had bone marrow involvement; 8 patients with only large cell
lymphoma, 4 with a predominant large cell component mixed with a small
cleaved cell component, and 6 with small cleaved cell involvement. By
the Ann Arbor system, there were 26 stage I patients, 22 stage II, 29 stage III, and 23 stage IV. Thirteen had constitutional symptoms.
Elevated LDH or 2M were present in 30% and 12%, respectively
(Table 1).
Response.
Eighty-five patients (85%) achieved a CR, 10 patients (10%) achieved
a PR, and 5 patients did not respond to initial therapy. Bone marrow
involvement, Ann Arbor stage IV, high 2M, high Tumor Score, and high
IPI score were significantly correlated with lower response (Table 1).
All nonresponders had a high Tumor Score or high/high-intermediate IPI
score. Four were women. All 5 nonresponders were over 65 years old,
with a median of 72 years old; other adverse pretreatment prognostic
factors included bone marrow involvement in 4, high LDH in 2, and high
2M in 3 (of 4 with 2M data).
Failure-free survival.
Thirty-two patients eventually progressed, including 22 of the 85 CR
patients, 5 of the 10 PR patients, and all 5 nonresponders. At 5 years
the FFS is 67%; the median FFS has not been reached (Fig
1). For those 32 patients who progressed,
the median time to progression was 19 months. Several variables were
important to predict FFS (Table 1). The Ann Arbor stage IV group of 23 patients had a FFS at 5 years of 37%, significantly worse than other
stages (Fig 2). 2M and marrow
involvement were significant adverse factors, and both the Tumor Score
and IPI were valuable systems to divide the population into different
prognostic groups.
Survival and predictors of survival.
With a median follow-up of 67 months, the median survival is 141 months
with a 72% survival at 5 years (95% CI 62% to 82%). There are
currently 65 patients alive, and 35 patients who have died, including
28 who died of disease. Seven died of unrelated causes, including 2 patients who died of unknown reasons, 2 who died of a stroke, 2 of lung
cancer, and 1 patient who died of a heart attack; all 7 of these
patients had achieved CR and had no evidence of disease at the time of
their death. All 5 patients with primary refractory disease have died,
compared to 6 of the 10 PR patients, and 24 of the 85 CR patients.
Survival according to clinical features is indicated in Table 1.
Eighty-five percent of patients younger than 60 years old survived 5 years versus 57% of those 60 years old (P = .011). Stage
IV patients had significantly shorter survival than others; survival of
the 29 stage III patients was equivalent to the survival of the 48 stage I and stage II patients (Fig 3). High
serum LDH correlated with a worse survival: 50% of patients with high
LDH survived 5 years versus 82% of these patients with a normal LDH (P = .001). Serum 2M was also strongly correlated with
survival: only 12.5% of patients with a 2M level 3.0 mg % are
alive at 5 years versus 76% of those with 2M lower than 3 (P < .001). The extent of extranodal disease predicted the
survival as well, with 66%, 33%, and 0% survival at 5 years for 1, 2, and 3 extranodal sites, respectively, versus 78% for those without
extranodal disease (P = .0042). Bone marrow was the most
frequent single site of extranodal disease, and it was of prognostic
importance: of the 18 patients who had marrow involvement, 13 are dead,
and the 5-year survival is 41% versus 80% for those without bone
marrow involvement (P = .0019). Only 5 patients had stage IV
disease based on sites other than the bone marrow. Of these 5 patients,
4 are alive and 1 patient has died, but the numbers of patients and
events are too few to characterize the prognostic importance of
specific extranodal sites other than the marrow. The extent of the
follicular versus diffuse pattern of the node was not prognostically
important: the 30 patients with a follicular plus diffuse pattern had a
similar survival to the 65 patients with a homogeneous follicular large cell pattern, as did those 5 patients with a small cleaved cell component (P = .78). Other variables that were analyzed,
including sex, platelets, and the presence of bulky disease, were not
important as predictors in our analysis.
The distribution of patients according to the IPI and the Tumor Score
is indicated in Table 1: both models show, for FLCL, a significantly
worse prognosis for patients belonging to the higher risk groups (Figs
4 and 5).
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| Fig 4.
Survival according to Tumor Score. Adverse features in
the Tumor Score are Ann Arbor stage III-IV, 2M 3 mg%, high LDH,
B symptoms, and the number of bulky masses. Each adverse factor has a
score of 1. Low risk is defined as a tumor score of 0 or 1, high risk
is a score of 2.
|
|
Stage III and IV.
Because in our population the ratio of stages I-II versus III-IV was
higher than most published series, we analyzed specifically the 52 patients with stage III-IV disease to have more accurate data to
compare with other series. The median survival of the combined stage
III-IV group was 103.4 months with a 5-year survival of 63%. However,
the 29 stage III patients had a survival at 5 years of 71% versus 51%
for the 23 patients with stage IV (P < .05; Fig 3).
Relevant prognostic variables for the stage III-IV group are shown in
Table 2. LDH and 2M proved useful to
stratify stage III-IV patients according to risk for survival.
Unexpectedly, age did not predict for FFS, but it was important for
survival. Other variables, including gender, performance status,
constitutional symptoms, bulky masses, WBC count, and platelets were
not predictive of outcome.
Stages III and IV are grouped together as one adverse feature in both
the IPI and the Tumor Score prognostic models. We examined, in our
stage III-IV patients, the remaining features of the Tumor Score model
for their prognostic relevance. By the Tumor Score system, of 11 patients with two or more additional adverse features besides stage,
the survival at 5 years was 33% versus 64% for those 29 patients with
only 0 to 1 additional adverse features (P = .018). Thus,
even in this group, the Tumor Score was able to capture a group with
poor prognosis. Likewise, the IPI was useful to stratify stage III-IV
patients into prognostic groups (Table 2).
| |
DISCUSSION |
In our current report on 100 patients with FLCL, the survival was 72%
at 5 years (median, 141 months). Another recent large series, by Wendum
et al,6 reported a 5-year survival of 58% and a median
survival of 73 months in their analysis of 89 patients with FLCL. When
compared with our population, there were a few differences: our
population was somewhat older, with 46% of patients older than 60 versus 35% in their report; conversely, only 52% of our patients
presented with Ann Arbor stage III-IV versus 74% in their study. To
facilitate comparisons with other series, we performed a separate
analysis of our subset of patients with stage III-IV disease: in these
52 patients, the median survival was 103 months with 63% alive at 5 years.
One interesting observation in the current series was the significantly
different outcome of stage III and stage IV patients. In our series,
patients with Ann Arbor stage III had a better survival than those with
stage IV (71% v 51% at 5 years, respectively), as well as a
better FFS (62% v 37%, respectively). Both the Tumor Score
and IPI prognostic models incorporate stage III-IV as one (equivalent)
adverse feature. Our data suggest that to group stage III and IV FLCL
patients together may not be totally correct. If this finding is
confirmed in other series, this observation might warrant different
therapeutic approaches for stage III and stage IV patients.
Besides stage, other important prognostic factors identified in the
current series included older age, multiple sites of extranodal involvement, and elevation of serum LDH and 2M. These findings are
similar to what has been described by Wendum et al, and, of course,
these features are key components of two prognostic models for
aggressive lymphomas, the IPI and the Tumor Score. This observation highlights the similarities of FLCL and DLCL, although, notably, the
distribution of patients by risk group showed a lower fraction with
high risk than is seen in most DLCL series. Specifically, 13 patients
on the current series had high-intermediate risk with a 5-year survival
of 28%, and 2 had high risk with a 5-year survival of 0%. This
distribution among risk groups is similar to the FLCL series of
Bartlett et al.7
Among extranodal sites of disease, bone marrow was the most common in
our series, and it was a significant adverse prognostic factor. We had
previously noted, in another series from our institution,10 that marrow involvement itself did not confer a worse prognosis, and we
had suggested that in this respect FLCL resembled other follicular
lymphomas and contrasted to DLCL where bone marrow involvement predicts
a poor prognosis. Our current finding is thus different, and may be
explained in part by the paucity of patients with discordant disease in
the marrow in the prospective trials from which the current report
derives. Of the 18 patients with marrow disease, the majority had large
cell lymphoma in the marrow, which is more ominous than having marrow
involvement with only small cleaved cell lymphoma.23
Our observation of a possible plateau in the FFS curve in these FLCL
patients is in contrast to previous suggestions by some of a behavior
more typical of the low-grade follicular lymphomas, with their pattern
of constant relapses over time.9,11,14 However, our results
are consistent with those of others, who have noted a plateau in the
FFS curve in patients treated with anthracycline-based
chemotherapy.5-7 The criteria for classifying FLCL may be
important in identifying those with potentially curable disease: the
Nebraska Lymphoma Study Group, in an earlier report,9 did
not observe a convincing FFS plateau, but more recently5 the same group did observe an apparent plateau in the FFS curve, when
using Berard's criteria. The occurrence of four late relapses observed
in our series is similar to the small number of late relapses seen in
the intermediate-grade lymphomas as reported by Cabanillas et
al.24 The presence of a small cleaved cell component either
in the lymph node or in the marrow may be a risk factor for late
relapse, as previously observed.23 Of the 32 patients who
relapsed, the median time to relapse of 19 months in this series does
not differ from the DLCL population. Another suggestion of the similar
biology of FLCL and DLCL is provided by the recent observation that
expression of the Bcl-2 protein correlates with a poor prognosis in
FLCL,6 as has previously been reported for
DLCL.25
It is controversial whether the natural history of FLCL is more akin to
indolent follicular lymphomas or to DLCL.5-7,9,11,14 Perhaps it is best regarded as a transitional phase, as postulated by
Gall and Mallory26 57 years ago and Rappaport
et al27 43 years ago. Our data suggest that FLCL has a
natural history and response to treatment similar to DLCL. The
distribution of variables that predict the outcome suggests that FLCL
patients often present with better prognostic features than DLCL
patients. Risk systems for DLCL18,19 are useful in FLCL:
both the IPI and the Tumor Score stratify patients well, allowing for
innovative therapies to be considered to improve the outcome in the
poorer outcome groups, while for better prognosis patients, diminished
toxicity with standard effective therapy can be the focus. A meaningful fraction of FLCL patients may possibly be cured with the same treatment
regimens used for DLCL.
| |
ACKNOWLEDGMENT |
The authors thank Joyce Palmer for assistance in preparation of the
manuscript, and also collaborators from the Division of Radiation
Oncology, and past and present members of the Department of
Lymphoma/Myeloma, notably Drs W.S. Velasquez and F. Swan.
| |
FOOTNOTES |
Submitted July 14, 1998; accepted November 19, 1998.
Supported in part by National Cancer Institute Core Grant CA16672
awarded to the University of Texas M.D. Anderson Cancer Center.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to P. McLaughlin, MD, University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Box 68, Houston, TX 77030.
| |
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TOP
ABSTRACT
INTRODUCTION
